Summary Malignant melanoma is a highly aggressive disease with alarmingly high mortality rates. Although we have gained substantial understanding of genetic determinants of the melanoma, we have very limited knowledge of epigenetic mechanisms underlying melanoma metastasis. Therefore, this proposal aims to identify epigenetic modifications and factors involved in the process of metastasis and understand how they impart metastatic potential to cancer cells. The long term-goal is to be able to identify novel drug targets and develop diagnostic assays. During my previous training, I have gained some experience in studying epigenetic mechanisms during development and colon cancer initiation. I am keen to apply some of this experience in addressing this vital question using melanoma system. The Chin lab's expertise in utilizing genomic datasets and large scale screens to understand metastasis and the availability of multiple mouse models of melanoma provides me a perfect environment to address the scientific question of my interest. In this proposal I aim to understand epigenetic mechanisms underlying pro-metastatic properties of melanoma cells utilizing new epigenomic methods, powerful in vivo screens and mouse models. In Aim 1, I will elucidate the mechanism of the pro- metastatic action of RNF2 and assess its potential as a drug target. In Aim 2, I will determine the epigenomic landscape of non-metastatic cells and pro-metastatic cells in an effort to identify the cellular systems affected by pro-metastatic epigenetic changes. In Aim 3, I will take unbiased approach and use in vivo large scale screens in mice to identify epigenetic metastasis-promoters and suppressors. The mechanism for the `hits' from this screen will be studied as used for RNF2 in Aim 1 and 2. Overall, my training in epigenomic methods, mouse modeling and large scale in vivo screens will hone my scientific skills to prepare me for a successful independent career. In my independent phase, I will identify the mechanism of new metastasis-suppressors and promoters identified by proposed-screens. In addition, I will build mouse and zebrafish models to assess the ability of these genes as drug targets. In the end, by these studies I hope to identify new drug targets with epigenetic roles and possible epigenetic marks (on specific genomic loci) to use for devising new diagnostic methods.